TLR7 in Innate and Adaptive Immunity to Influenza 公开

Jeisy Scott, Victoria Jean (2012)

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TLR7 in Innate and Adaptive Immunity to Influenza
Toll-like receptor 7 (TLR7) is a major pattern recognition receptor involved in the
recognition of influenza A virus (IAV) infection due to its ability to sense ssRNA.
However, the role of TLR7 in the shaping of the humoral response to IAV
infection and vaccination is not well understood. I demonstrate that the absence
of TLR7 signaling leads to the induction of a Th2 polarized memory response to
IAV infection. This imbalance is likely due to the increased number of myeloid
derived suppressor cells (MDSCs) recruited to the site of infection, influencing
the programming of the subsequent adaptive response. Furthermore, I also
demonstrate that this Th2 bias in TLR7-/- mice is maintained long-term with a
decrease in memory IgM antibody secreting cells (ASCs). However, this Th2
polarization does not inhibit their ability to defend against a secondary IAV
challenge. In contrast, TLR7-mediated signaling during influenza vaccination was
important. In the absence of TLR7-mediated signaling, insufficient HA-specific
antibodies were induced and left mice vulnerable to IAV challenge. Hence, my
findings suggest that the addition of RNA or other TLR7 ligands to influenza
vaccines will improve their immunogenicity.

Table of Contents

Chapter 1 : Introduction 1

Innate Immunity 1

PRRs of the Innate Immune System 2

PRR signaling pathways 5

Figure 1-1: RIG-I and TLR7 signaling 6

Toll-like Receptors 8

Cellular mediators of immunological responses 13

Influenza Virus 19

Virus Lifecycle 24

Figure 1-2: Influenza Virus Lifecycle 27

Vaccines 27

TLR7 & IAV 32

Current Study 35

Chapter 2 : "Increased MDSC Accumulation and Th2 Biased Response to Influenza A Virus Infection in the Absence of TLR7 in Mice" 36

Figure 2-1: TLR7-/- mice exhibit increased influenza-induced morbidity. 48

Figure 2-2: The absence of TLR7 does not significantly alter influenza-induced inflammatory cytokine profiles. 49

Figure 2-3: Increased recruitment of Gr1+ CD11b+ cells to the lungs of TLR7-/- mice. 51

Figure 2-4: Recruitment of lymphocytes and macrophages to lungs was not significantly affected in TLR7-/- mice. 52

Figure 2-5: Functional analysis of lung-derived MDSCs shows greater activity in TLR7-/- mice. 54

Figure 2-6: Increased expansion of germinal center B cells in TLR7-/- mice. 56

Figure 2-7: Absence of TLR7 leads to increased numbers of IL-4 producing CD4+ T cells. 57

Figure 2-8: The frequency of NP-specific CD8+ T cells are not affected in TLR7-/- mice. 58

Figure 2-9: No changes in cytokine expression were observed in splenocytes on day 10 post-infection. 59

Figure 2-10: Th2 polarization in TLR7-/- mice alters IgG isotype switching of influenza-specific antibodies. 60

Figure 2-11: TLR7 inhibition of MDSC mediated Th1 suppression. 66

Chapter 3 : "TLR7 recognition is dispensable for influenza virus A infection, but important for the induction of hemagglutinin-specific antibodies in response to the 2009 pandemic split vaccine in mice." 68

Figure 3-1: TLR7-/- and MyD88-/- mice had fewer GC-B cells and PR8-specific IgM+ ASCs following primary infection. 79

Figure 3-2: TLR7-/- and MyD88-/- mice had comparable levels of PR8-specific CD8 T cells following IAV infection. 80

Figure 3-3: TLR7-/- mice had reduced GC reaction and lower frequencies of IgM+ BM PR8-specific ASCs following a lethal IAV challenge. 83

Figure 3-4: TLR7-/- and MyD88-/- mice had comparable levels of PR8-specific and cytokine secreting T cells following challenge. 84

Figure 3-5: TLR7-/- and MyD88-/- mice had lower levels of circulating IAV-specific IgM, yet comparable levels of IAV-specific IgG and HI titers following IAV infection. 87

Figure 3-6: The B-cell response to pandemic split vaccine was compromised in TLR7-/- mice. 89

Figure 3-7: The T-cell response in vaccinated mice was comparable following vaccination in the presence or absence of TLR7 signaling. 90

Figure 3-8: The A(H1N1)pdm09 Split vaccine contains viral genomic RNA. 91

Figure 3-9: TLR7 recognition contributed to the B cell response to split influenza vaccine. 92

Figure 3-10: TLR7-/- mice failed to develop protective immunity following immunization. 94

Chapter 4 : Discussion 100

Figure 4-1: B cell Signal 3 Hypothesis 109

Chapter 5 : References 110

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